Chronic Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade
Effects on Cardiovascular Remodeling in Rats Induced by the Long-term Blockade of Nitric Oxide Synthesis
Abstract We have shown previously that angiotensin-converting enzyme (ACE) inhibitors prevent coronary vascular remodeling (medial thickening and perivascular fibrosis) and myocardial remodeling (fibrosis and hypertrophy) in rats induced by long-term inhibition of nitric oxide (NO) synthesis with oral administration of Nω-nitro-l-arginine methyl ester (L-NAME). ACE inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin. In this study, we aimed to determine the relative contribution of the latter two mechanisms to the beneficial effects of an ACE inhibitor on structural remodeling. First, we examined the effects of the ACE inhibitor temocapril and the angiotensin II AT1 subtype receptor antagonist CS-866 on the structural remodeling induced by administering L-NAME for 8 weeks. Temocapril and CS-866 were equally effective in preventing remodeling. Second, we examined whether the effect of temocapril on the remodeling induced by L-NAME was reduced by the bradykinin receptor antagonist HOE140. The latter drug did not alter the beneficial effect of temocapril on remodeling. In conclusion, although species differences must be considered to apply our conclusion to clinical conditions, the present results suggest that the inhibition of angiotensin II activity, mediated via the AT1 receptors, is responsible for the beneficial effects of an ACE inhibitor in our animal model of coronary vascular and myocardial remodeling induced by the long-term inhibition of NO synthesis.
Nitric oxide derived from the endothelium is important in maintaining the homeostasis of the blood vessel wall.1 2 3 4 In addition to its role in controlling vascular tone, extensive evidence suggests that NO inhibits platelet aggregation, thrombus formation, leukocyte adhesion, and blood vessel proliferation.1 2 3 4 Studies in animals and humans have shown that cardiovascular disorders such as hypertension, hypercholesterolemia, and atherosclerosis are associated with the abnormal production of NO (endothelial dysfunction) of the large epicardial and resistance coronary arteries.5 6 7 8 9 Thus, the inhibition of NO synthesis may contribute to functional and structural changes of the coronary vasculature in pathological conditions.
We10 11 12 and other investigators13 14 15 have reported that the long-term blockade of NO synthesis with chronically administered L-NAME produces vascular structural changes (thickening of the media and perivascular fibrosis) and hypertrophy and fibrosis of the myocardium in animals. More recently, we have reported that the increase in tissue ACE activity precedes the development of vascular and myocardial remodeling and that ACEIs, but not hydralazine, prevent the coronary vascular and myocardial remodeling observed in this experimental model.16 Michel et al17 also have demonstrated that ACEIs prevent the vascular structural changes in the kidney and spinal cord induced by long-term administration of L-NAME. Evidence indicates therefore that activation of tissue ACE activity plays an important role in mediating the cardiac remodeling observed in certain disorders.
There are two possible mechanisms by which ACEIs might have exerted their beneficial effects in those studies: (1) inhibition of Ang II formation and (2) inhibition of bradykinin breakdown. Ang II produces vascular and myocardial fibroproliferative changes via an action on the AT1 receptor subtype.18 19 The increase in bradykinin concentration resulting from inhibition of its breakdown by ACEIs20 would increase NO synthesis via stimulation of the bradykinin B2 receptor subtype and therefore may contribute to the inhibition of vascular and myocardial structural changes. Evidence suggests that vascular tissue contains an intrinsic kinin-kallikrein system21 and that endogenous bradykinin contributes to the endothelium-dependent and flow-mediated dilation of human coronary circulation in vivo.22 However, it is not known whether the beneficial effects of an ACEI observed in our model result from inhibition of Ang II–induced actions, the catabolism of bradykinin, or both.
The purpose of this study was to determine the relative roles of Ang II and bradykinin in the effects of an ACEI on vascular and myocardial remodeling in rats induced by long-term administration of an NO synthase inhibitor. Our specific aims were (1) to examine whether a selective antagonist of the Ang II type 1 receptors caused the similar effects as ACEIs and (2) to examine whether the beneficial effects of an ACEI were reduced by a selective antagonist of the bradykinin receptor.
These experiments were reviewed and approved by the Committee on Ethics of Animal Experiments, Faculty of Medicine, Kyushu University, and conducted according to the Guidelines for Animal Experiments of the Faculty of Medicine, Kyushu University and Law No. 105 and Notification No. 6 of the Japanese Government.
L-NAME was purchased from Sigma. The ACE inhibitor temocapril23 and the Ang II AT1 receptor antagonist CS-86624 were gifts from Sankyo Pharmaceutical Co. The bradykinin B2 receptor antagonist HOE14025 was a gift from Hoechst Pharmaceutical Co..
Experimental Animal Preparation
Male Wistar-Kyoto rats (20 weeks old, 320 to 350 g) were obtained from an established colony at the Animal Research Institution of Kyushu University Faculty of Medicine. Eight groups of rats (20 to 25 animals in each group) were studied. The control group received untreated regular chow and drinking water. The second group (L) received L-NAME in its drinking water (1 mg/mL). At this concentration, the daily intake of L-NAME for the latter group was approximately 30 to 40 mg/d. The third group (L+ACEI) received L-NAME and 0.1 mg/mL temocapril in its drinking water. The fourth group (L+ATRA1) received L-NAME in its drinking water and a high dose (75 μg/g) of CS-866 in its chow. The fifth group (L+ATRA2) received L-NAME in its drinking water and a low dose (7.5 μg/g) of CS-866 in its chow. The sixth group (ATRA) received CS-866 alone (7.5 μg/g) in its chow. The doses of temocapril and CS-866 were determined empirically, but we found them to be effective as described below. The seventh group (L+ACEI+HOE) received L-NAME, temocapril, and HOE140 at 70 μg/kg per day infused by an osmotic minipump. The eighth group (HOE) received HOE140 alone by the minipump. The minipump was implanted in the peritoneal cavity under anesthesia 2 days before the initiation of treatment. This dose of HOE140 has been used successfully by other investigators.26 All rats were single-housed in a special pyrogen-free facility. We monitored and confirmed that the rats drank approximately 30 to 40 mL of water and ate 20 g of chow regardless of the treatment. We also confirmed that their drinking and eating patterns were unaffected by any treatment protocol.
To determine whether the dose of HOE140 was sufficient to inhibit the vascular effect of bradykinin, we examined the bradykinin-induced decrease in arterial pressure with and without HOE140 treatment. At the eighth week of treatment, eight rats each from the L+ACEI and the L+ACEI+HOE groups were anesthetized with pentobarbital. Catheters (PE-50) were placed in a carotid artery to measure the pressure and into a jugular vein to administer drugs. Blood pressure was measured by a calibrated pressure transducer (Nihon-Kohden Inc). All rats were pretreated with temocaprilat (200 μg/kg IV) to potentiate the effect of bradykinin. After the blood pressure stabilized, bradykinin (100 ng in 0.1 mL saline) was administered intravenously, and the change in blood pressure was recorded. In this preliminary study, the intravenous administration of bradykinin reduced the mean arterial pressure by 31±2 mm Hg in the L+ACEI group and by 2±2 mm Hg in the L+ACEI+HOE group (P<.01), indicating that HOE140 blocked the bradykinin-induced dilation of the systemic vasculatures under the experimental conditions.
Systolic blood pressure (the tail-cuff method), heart rate, and body weight were measured every week. Morphometric, immunohistochemical, and biochemical analyses were performed at the eighth week of treatment.
Histopathology and Morphometry
Histopathology and morphometry were performed by a single investigator who was blind to all treatment protocols. Findings were evaluated in 10 rats from each group as previously described.16 After each animal was anesthetized with pentobarbital, its abdomen was opened and the abdominal aorta was cannulated. The chest was opened and an incision made in the right atrium. The heart was perfused via the aorta with oxygenated Krebs’ solution at a pressure of 90 mm Hg, and then the coronary vasculature was fixed for 30 minutes with 6% formaldehyde solution. After completion of the fixation, the heart was removed, the left and right ventricles were separated from the atria, and the great vessels and were weighed. The left ventricle was cut into five pieces perpendicular to its long axis. All tissues were fixed in 6% formaldehyde for a few days and then dehydrated, embedded in paraffin, and cut into 5-μm-thick slices that were mounted on slides and stained with hematoxylin-eosin and Masson’s trichrome staining solutions. The whole areas of all histopathologic sections were scanned using a light microscope (Microphot-FXA, Nikon Co) equipped with a computer-based image analyzer.
To evaluate the thickening of the coronary arterial wall and perivascular fibrosis, short-axis images of the large (ID >200 μm) and small coronary arteries (ID <200 μm) were studied. The inner border of the lumen and the outer border of the tunica media were traced at 100× to 200× magnification in each arterial image, and the areas encircled by the tracings were calculated. During the quantification procedure, only round vessels were studied and any nonround vessels due to oblique transsection or branching were excluded. We then calculate the wall-to-lumen ratio (defined as the medial thickness of the vessel divided by its internal diameter) and the area of fibrosis (defined as amount of collagen deposition stained with aniline blue that immediately surrounded the blood vessels) of the blood vessels. Perivascular fibrosis was determined as the ratio of the area of fibrosis surrounding the vessel wall to the total vessel area. In each heart, approximately 40 small arteries and 10 large arteries were examined. Average values for each size of vessel were used for analysis.
Myocardial interstitial fibrosis was determined by quantitative morphometry.16 Each section was scanned at 400× magnification. The collagen fraction was calculated as the sum of the total area of interstitial fibrosis in the entire visual field of the section divided by the sum of the total connective tissue area plus the myocardial area in the entire visual field of the section. The areas of perivascular fibrosis and reparative fibrosis, which were clearly distinguishable from myocardial interstitial fibrosis, were excluded from this latter measurement. The reparative fibrosis that follows myocyte necrosis was also determined in this study at 10× magnification.16 The areas of myocardial reparative fibrosis were determined. This area was calculated as the sum of the total areas of fibrosis in the entire visual field of the section divided by the sum of the total area of connective tissue plus the myocardial area in the entire visual field of the section. The areas of perivascular fibrosis in arteries and veins were excluded from the latter measurements.
Morphometry of left ventricular myocytes was performed to measure the myocyte cross-sectional area.16 This morphometry was done on sections of the lateral mid-free wall of the left ventricle. The myocyte cross-sectional area was measured from myocytes that were cut transversely and had both a visible nucleus and an unbroken cellular membrane. The outer borders of the myocytes were traced, and the myocyte areas were calculated. Approximately 100 cells were counted per heart, and the average value was used for analysis.
Biochemical analysis was performed on 10 separate rats from each group. At the eighth week of treatment, the animals were anesthetized and a blood sample was taken from the femoral artery. The chest was then opened and the heart removed. The left ventricle was put into liquid nitrogen. Serum and tissue ACE activities were measured by the rate of generation of His-Leu from a hippuryl-His-Leu substrate using a fluorometric assay.27
Data are expressed as mean±SEM. Paired data were compared by Student’s t tests. Differences in a single parameter among groups (myocyte size, heart weight, etc.) were compared by using a one-way ANOVA followed by a Bonferroni test for multiple comparisons. Differences in multiple parameters (eg, changes in blood pressure and body weight) among groups were compared with a two-way ANOVA followed by a Bonferroni multiple-comparison t test. A level of P<.05 was considered statistically significant.
Body Weight and Hemodynamic Variables
Body weights did not differ significantly among the groups before treatment (Table⇓). During the study, rats in the control, HOE, and ATRA groups gained weight, whereas those in the L group lost weight. The body weight of the L+ACEI, L+ATRA1, L+ATRA2, and L+ACEI+HOE groups showed no significant change during the study.
Changes in systolic arterial pressure are shown in Fig 1⇓. The L group showed a progressive rise in systolic arterial pressure. Increases in systolic arterial pressure observed in the L+ATRA2 group resembled those in the L group. The systolic arterial pressure showed no significant change in the control, L+ACEI, L+ATRA1, L+ACEI+HOE, ATRA, or HOE group. The heart rates were similar among the eight groups throughout the treatments (Table⇑).
Coronary Vascular Remodeling
Micrographs of the coronary arteries obtained in the control, L, L+ATRA1, L+ACEI, and L+ACEI+HOE groups are shown in Fig 2⇓. The wall-to-lumen ratios and the perivascular fibrosis in the coronary arteries were significantly greater after the eighth week of treatment in the L group than in the control group. These vascular structural changes were reduced significantly by treatment with ACEI, as well as by the low and high doses of ATRA (Fig 3⇓). Treatment with ATRA alone had no effect on the coronary vascular structure. Treatment with HOE140 did not alter the beneficial effect of ACEI (Fig 3⇓). Treatment with HOE140 alone did not affect coronary vascular structure.
Myocardial Interstitial and Reparative Fibrosis
Both myocardial interstitial fibrosis and reparative fibrosis were increased significantly at the eighth week of treatment in the L group (see Fig 4⇓). These two types of cardiac fibrosis were significantly reduced by treatment with ACEI as well as by the low and high doses of ATRA. Treatment with ATRA alone did not alter the cardiac fibrosis. Treatment with HOE140 did not alter the beneficial effect of ACEI (Fig 4⇓). Treatment with HOE140 alone had no effect on cardiac fibrosis.
The relative weights of the left and right ventricles and the cross-sectional areas of the myocytes were increased significantly in the L group (Fig 5⇓). The increases in these parameters induced by long-term administration of L-NAME were blunted to a similar extent by ACEI and by both the low and the high doses of ATRA. The relative left and right ventricular weights and the myocyte areas in the ATRA group did not differ significantly from those of the control group. The prevention of the myocardial hypertrophy induced by ACEI was not altered by HOE140 (Fig 5⇓). Treatment with HOE140 alone did not affect the relative ventricular weights or the myocyte cross-sectional area.
Serum and Cardiac Tissue ACE Activity
Serum ACE activity was decreased significantly in the L+ACEI and L+ACEI+HOE groups compared with the control group but it was not altered significantly in other groups (Table⇑). ACE activity was markedly increased in the cardiac tissue of the L group (Table⇑). The increase in ACE activity in cardiac tissue was blunted by ACEI and by both the low and the high doses of CS-866. Treatment with CS-866 alone did not alter cardiac ACE activity. Treatment with HOE140 did not alter the effect of ACEI on cardiac ACE activity. Treatment with HOE140 alone had no effect on cardiac ACE activity.
We recently showed that the local expression of ACE plays a key role in the pathogenesis of the coronary vascular remodeling (medial thickening and perivascular fibrosis) and myocardial remodeling (fibrosis and myocyte hypertrophy) induced in rats by the long-term administration of L-NAME.16 ACE converts Ang I to Ang II and inhibits the catabolism of bradykinin.20 Ang II stimulates18 19 28 whereas bradykinin20 inhibits the cardiac fibroproliferative responses. The present study sought to determine the relative contributions of Ang II and bradykinin to the beneficial effects of the ACEI temocapril in our model. First, we found that the AT1 receptor antagonist and the ACEI were equally effective in reducing systolic arterial pressure and attenuating the coronary vascular and myocardial structural changes induced by the long-term administration of L-NAME. Second, we challenged the beneficial effects of temocapril with HOE140, which did not alter the effects of temocapril on systolic arterial pressure, structural changes, or ACE activities. The latter findings suggest that bradykinin did not participate in the effect of the ACEI in our experiments. We interpret these findings as indicating that the increased cardiac ACE expression and subsequent activation of AT1 receptors are responsible for the beneficial effects of the ACEI on preventing the structural changes in the coronary vasculature and myocardium in our model.
Several reports have demonstrated that the effects of ACE inhibition on cardiovascular remodeling are different from those of AT1 receptor antagonism. Spinale et al29 30 showed that an effect of AT1 receptor blockade was less than ACE inhibition on cardiac dilatation and myocardial dysfunction in a canine model of pacing-induced heart failure. McDonald et al31 showed that in dogs with hypertrophic remodeling after direct current shock injury the ACE inhibition attenuates hypertrophic remodeling, but the AT1 receptor inhibition did not affect hypertrophic remodeling. Weinberg et al32 33 demonstrated that the ACE inhibition, but not AT1 inhibition, regressed left-ventricular hypertrophy in rats with persistent systolic pressure overload due to ascending aortic stenosis. In contrast, both ACE inhibition and AT1 antagonism have been shown to display similar inhibitory effects on hypertrophic remodeling in rats after myocardial infarction34 and in rats with ascending aortic banding35 when drugs were used at high doses to reduce systolic arterial pressure. Thus, in those rat models with hypertrophic remodeling,34 35 the effects of AT1 receptor antagonists seem to result at least in part from the reduction in systolic loading conditions. In the present study, however, a low dose of the AT1 receptor antagonist did not affect the increase in systolic blood pressure but rather produced an inhibitory effect identical to that observed with an antihypertensive dose of the AT1 receptor antagonist. Thus, the change in systolic arterial pressure was not responsible for its effects in our experimental model.
The relative roles of Ang II and bradykinin in the pathogenesis of clinical disorders (hypertension, cardiovascular remodeling, and heart failure) are unclear. There is considerable debate concerning the relative contribution of Ang II and bradykinin to the effect of ACEIs on experimental cardiovascular remodeling. Linz and Scholkens36 showed that the specific bradykinin receptor antagonist completely restored the effects of ACE inhibition on preventing the development of left ventricular hypertrophy in rats induced by abdominal aortic banding, whereas AT1 receptor antagonist was less effective than ACEI. Farhy et al26 suggested that the beneficial effect of ACEIs on vascular neointimal formation after balloon injury was due to both the blockade of Ang II formation and the catabolism of bradykinin. In this study, the effects of the ACEI on cardiovascular structural changes were not altered by the bradykinin receptor antagonist. We speculate, therefore, that the relative contributions of the inhibition of Ang II activity and the increase of bradykinin’s effect to the beneficial effects of ACEIs depend on the experimental model as well as on the degree of activation of local and systemic renin-angiotensin systems. In addition, we must take species differences into account when applying those experimental findings to clinical conditions.
We considered the possibility that the inhibitory effect of the AT1 receptor antagonist on the cardiac structural changes induced by L-NAME was not due solely to AT1 receptor antagonism. It may be possible that the decreased cardiac ACE activity observed in response to the AT1 receptor antagonist treatment also contributed to the overall beneficial effect of the AT1 receptor antagonist on the cardiac structural changes evoked by the chronic administration of L-NAME. The mechanism by which an AT1 receptor antagonist reduced ACE activity is not known from our study, but it is possible that it was secondary to the improvement in the structural changes mediated by AT1 receptor blockade.
The mechanism by which the renin-angiotensin system is activated after the long-term administration of L-NAME was not explored in the present study. Reports from our laboratory have shown that the increases in both cardiac tissue ACE activity16 and cardiac tissue AT1 receptor number37 precede the development of cardiac structural changes observed in our model. Further studies are needed to elucidate the pathophysiological factors responsible for the upregulation of the local renin-angiotensin system in our experimental model.
In conclusion, the results of the present study indicate that inhibition of Ang II activity, which is mediated by AT1 receptors, is responsible for the beneficial effects of the ACEI temocapril in our model.
Selected Abbreviations and Acronyms
|ACEI||=||angiotensin-converting enzyme inhibitor|
|AT1, AT2||=||angiotensin type 1, type 2|
|L-NAME||=||Nω-nitro-l-arginine methyl ester|
This study was supported by grants-in-aid for scientific research (06670725, 06404034, and 07557346) from the Ministry of Education, Science, and Culture, Tokyo, Japan; by the Mitsukosi grant-in-aid 1996 from Mitsukoshi Foundation, Tokyo, Japan; by a research grant from Cell Science Foundation, Osaka, Japan; by a research grant from Suzuken Memorial Foundation, Nagoya, Japan; and by a research grant from Kanae Foundation of Research for New Medicine, Osaka, Japan.
- Received March 11, 1997.
- Revision received April 1, 1997.
- Accepted June 12, 1997.
Dzau VJ, Gibbons GH. Endothelium and growth factors in vascular remodeling of hypertension. Hypertension. 1991;18(suppl III):III-115-III-121.
Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai H, Sugimachi M, Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest. 1993;91:29–37.
Egashira K, Inou T, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Kuga T, Urabe Y, Takeshita A. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine. Circulation. 1993;88:77–81.
Egashira K, Suzuki S, Hirooka Y, Kai H, Sugimachi M, Imaizumi T, Takeshita A. Impaired endothelium-dependent vasodilation of large epicardial and resistance coronary arteries in patients with essential hypertension. Different responses to acetylcholine and substance P. Hypertension. 1995;25:201–206.
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Takeshita A. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasodilation in patients with hypercholesterolemia. Circulation. 1994;89:2519–2524.
Zeiher AM, Drexler H, Saubier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993;92:652–662.
Ito A, Egashira K, Kadokami T, Fukumoto Y, Takayanagi T, Nakaike R, Kuga T, Sueishi K, Shimokawa H, Takeshita A. Chronic inhibition of endothelium-derived nitric oxide synthesis causes coronary microvascular structural changes and hyperreactivity to serotonin in pigs. Circulation. 1995;92:2636–2644.
Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, Takeshita A. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension. 1995;26(part 1):957–962.
Kadokami T, Egashira K, Kuwata K. Altered serotonin receptor subtypes contribute to microvascular hyperreactivity to serotonin in pigs with chronic inhibition of nitric oxide. Circulation. 1996;94:182–189.
Arnal JF, Warin L, Michel JB. Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. J Clin Invest. 1992;90:647–652.
Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992;90:278–281.
Ribeiro MO, Antunes E, Nicci G, Lovisolo SM, Zatz R. Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension. 1992;20:298–303.
Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest. 1997;99:278–287.
Griendling KK, Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulation. 1993;87:1816–1828.
Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993;73:413–423.
Erdös EG. Angiotensin converting enzyme and the change in our concept through the years. Hypertension. 1990;26:363–370.
Oza NB, Schwartz JH, Goud HD, Levinsky NG. Rat aortic smooth muscle cell in culture express kallikrein kininogen and bradykininase activity. J Clin Invest. 1990;85:597–600.
Groves P, Kurz S, Just H, Drexler H. Role of bradykinin in human coronary vasomotor control. Circulation. 1995;92:3424–3430.
Farhy RD, Carretero OA, Ho KL, Scicli G. Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res. 1993;72:1202–1210.
Cheung HS, Cushman DW. Inhibition of homogenous angiotensin-converting enzyme of rabbit lung by synthetic venom peptides of Bothrops jararaca. Biochim Biophys Acta. 1973;293:451–463.
Hou J, Kato H, Cohen RA, Chobanian AV, Brecher P. Angiotensin II-induced cardiac fibrosis in rats is increased by chronic inhibition of nitric oxide synthase. J Clin Invest. 1995;96:2469–2477.
Spinale FG, Holzgrefe HH, Mukherjee R, Hird RB, Walker JD, Arnim-Barker A, Powell JR, Koster WH. Angiotensin-converting enzyme inhibition and the progression of congestive cardiomyopathy: effects on left ventricular and myocyte structure and function. Circulation. 1995;92:562–578.
Spinale FG, Holzgrefe HH, Hird RB, Walker JD, Arnim AE, Eble DM, Powell JR, Koster WH. Differential effects of ACE inhibition and AT1 angiotensin II receptor blockade on LV and myocyte function and structure with dilated cardiomyopathy. Circulation. 1994;90:I-III.
McDonald KM, Garr M, Carlyle PF, Francis GS, Hauer K, Hunter DW, Parish T, Stillman A, Cohn JN. Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation. 1994;90:3034–3046.
Weinberg EO, Schoen FJ, George D, Kagaya Y, Douglas PS, Litwin SE, Schunkert H, Benedict CR, Lorell BH. Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation. 1994;90:1410–1422.
Weinberg WO, Lee MA, Weigner M, Lindpaintner K, Bishop SP, Benedict CR, Ho KKL, Douglas PS, Chafizadeh E, Lorell BH. Angiotensin AT1 receptor inhibition. Effects on hypertrophic remodeling and ACE expression in rats with pressure-overload hypertrophy due to ascending aortic stenosis. Circulation. 1997;95:1592–1600.
Schieffer B, Wirger A, Meybrunn M, Seitz S, Holtz J, Riede UN, Drexler H. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation. 1994;89:2273–2282.
Bruckschlegel G, Holmer SR, Jandeleit K, Grimm D, Muders F, Kromer EP, Riegger AJ, Schunkert H. Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension. 1995;25:250–259.
Katoh M, Egashira K, Usui M. Cardiac angiotensin II receptors is increased in rats with cardiac remodeling induced by long-term blockade of nitric oxide synthesis. Circulation. 1996;94(suppl 1):I-656.